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Background: Discovering biological markers is essential for understanding and treating mental disorders. Despite the limitations of current non-invasive methods, neural progenitor cells from the olfactory epithelium (hNPCs-OE) have been emphasized as potential biomarker sources. This study measured soluble factors in these cells in Major Depressive Disorder (MDD), Borderline Personality Disorder (BPD), and healthy controls (HC). Methods: We assessed thirty-five participants divided into MDD (n=14), BPD (n=14), and HC (n=7). MDD was assessed using the Hamilton Depression Rating Scale. BPD was evaluated using the DSM-5 criteria and the Structured Clinical Interview for Personality Disorders. We isolated hNPCs-OE, collected intracellular proteins and conditioned medium, and quantified markers and soluble factors, including Interleukin-6, interleukin-8, and others. Analysis was conducted using one-way ANOVA or Kruskal-Wallis test and linear regression. Results: We found that hNPCs-OE of MDD and BPD decreased Sox2 and laminin receptor-67 kDa levels. MASH-1 decreased in BPD, while tubulin beta-III decreased in MDD compared to controls and BPD. Also, we found significant differences in IL-6, IL-8, MCP-1, and thrombospondin-1 levels between controls and MDD, or BPD, but not between MDD and BPD. Conclusions: Altered protein markers are evident in the nhNPCs-OE in MDD and BPD patients. These cells also secrete higher concentrations of inflammatory cytokines than HC cells. The results suggest the potential utility of hNPCs-OE as an in vitro model for researching biological protein markers in psychiatric disorders. However, more extensive validation studies are needed to confirm their effectiveness and specificity in neuropsychiatric disorders.
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Melatonin is a hormone synthesized by the pineal gland with neuroprotective and neurodevelopmental effects. Also, melatonin acts as an antidepressant by modulating the generation of new neurons in the dentate gyrus of the hippocampus. The positive effects of melatonin on behavior and neural development may suggest it is used for reverting stress but also for the alterations produced by chemotherapeutic drugs influencing behavior and brain plasticity. In this sense, temozolomide, an alkylating/anti-proliferating agent used in treating brain cancer, is associated with decreased cognitive functions and depression. We hypothesized that melatonin might prevent the effects of temozolomide on depression- and anxiety-like behavior by modulating some aspects of the neurogenic process in adult Balb/C mice. Mice were treated with temozolomide (25 mg/kg) for three days of two weeks, followed by melatonin (8 mg/kg) for fourteen days. Temozolomide produced short- and long-term decrements in cell proliferation (Ki67-positive cells: 54.89% and 53.38%, respectively) and intermediate stages of the neurogenic process (doublecortin-positive cells: 68.23% and 50.08%, respectively). However, melatonin prevented the long-term effects of temozolomide with the increased number of doublecortin-positive cells (47.21%) and the immunoreactivity of 2' 3'-Cyclic-nucleotide-3 phosphodiesterase (CNPase: 82.66%), an enzyme expressed by mature oligodendrocytes, in the hilar portion of the dentate gyrus. The effects of melatonin in the temozolomide group occurred with decreased immobility in the forced swim test (45.55%) but not anxiety-like behavior. Thus, our results suggest that melatonin prevents the harmful effects of temozolomide by modulating doublecortin cells, hilar oligodendrocytes, and depression-like behavior tested in the forced swim test. Our study could point out melatonin's beneficial effects for counteracting temozolomide's side effects.
Assuntos
Depressão , Melatonina , Animais , Camundongos , 2',3'-Nucleotídeo Cíclico 3'-Fosfodiesterase , Depressão/induzido quimicamente , Depressão/tratamento farmacológico , Proteínas do Domínio Duplacortina , Melatonina/farmacologia , Camundongos Endogâmicos BALB C , Neurônios , Temozolomida/efeitos adversos , Temozolomida/farmacologiaRESUMO
Depression is the most common affective disorder worldwide, accounting for 4.4% of the global population, a figure that could increase in the coming decades. In depression, there exists a reduction in the availability of dendritic spines in the frontal cortex (FC) and hippocampus (Hp). In addition, histone modification and DNA methylation are also dysregulated epigenetic mechanisms in depression. Repetitive transcranial magnetic stimulation (rTMS) is a technique that is used to treat depression. However, the epigenetic mechanisms of its therapeutic effect are still not known. Therefore, in this study, we evaluated the antidepressant effect of 5 Hz rTMS and examined its effect on dendritic remodeling, immunoreactivity of synapse proteins, histone modification, and DNA methylation in the FC and Hp in a model of chronic mild stress. Our data indicated that stress generated depressive-like behaviors and that rTMS reverses this effect, romotes the formation of dendritic spines, and favors the presynaptic connection in the FC and DG (dentate gyrus), in addition to increasing histone H3 trimethylation and DNA methylation. These results suggest that the antidepressant effect of rTMS is associated with dendritic remodeling, which is probably regulated by epigenetic mechanisms. These data are a first approximation of the impact of rTMS at the epigenetic level in the context of depression. Therefore, it is necessary to analyze in future studies as to which genes are regulated by these mechanisms, and how they are associated with the neuroplastic modifications promoted by rTMS.
Assuntos
Lobo Frontal , Estimulação Magnética Transcraniana , Hipocampo , Metilação de DNA , Epigênese GenéticaRESUMO
BACKGROUND: The concept of environmental enrichment (EE) encompasses complex physical, social, cognitive, motor, and somatosensory stimuli to which individuals are differentially exposed. An indicator of EE comprising these elements would facilitate the study of the impact of EE in diverse clinical settings by allowing an easy and comparable measurement. This study aimed to create and test such an EE indicator based on the Florida Cognitive Activities Scale (FCAS), the Multidimensional Social Integration in Later Life Scale (SILLS), and the International Physical Activity Questionnaire (IPAQ). METHODS: Participants with major depression and control subjects were recruited in this cross-sectional comparative study. Depressive symptom severity was assessed with the Hamilton Depression Rating Scale (HAM-D). The EE indicator was used to evaluate cognitive, social, and physical activity. We divided the sample into three levels of cognitive and social activities to construct an EE indicator and compared the obtained scores between participants with major depression and control subjects. RESULTS: 40 patients suffering from major depression and 50 control subjects were included. Higher HAM-D scores were associated with lower EE levels. Cognitive and social items exhibited adequate reliability. Control subjects reported higher scores in all three activities evaluated, except for some items of physical activities. This indicator of EE clearly differentiated between participants with major depression from control subjects. CONCLUSIONS: FCAS, SILLS, and IPAQ used together are valid to evaluate EE. This EE indicator may be a useful tool during clinical practice. The cross-sectional design and the small sample size are limitations of the present study.
Assuntos
Transtorno Depressivo Maior , Cognição , Estudos Transversais , Transtorno Depressivo Maior/diagnóstico , Humanos , Reprodutibilidade dos TestesRESUMO
Depression is a neuropsychiatric disorder with a high impact on the worldwide population. To overcome depression, antidepressant drugs are the first line of treatment. However, pre-clinical studies have pointed out that antidepressants are not entirely efficacious and that the quality of the living environment after stress cessation may play a relevant role in increasing their efficacy. As it is unknown whether a short daily exposure to environmental enrichment during chronic stress and antidepressant treatment will be more effective than just the pharmacological treatment, this study analyzed the effects of fluoxetine, environmental enrichment, and their combination on depressive-associated behavior. Additionally, we investigated hippocampal neurogenesis in mice exposed to chronic mild stress. Our results indicate that fluoxetine reversed anhedonia. Besides, fluoxetine reversed the decrement of some events of the hippocampal neurogenic process caused by chronic mild stress. Conversely, short daily exposure to environmental enrichment changed the deterioration of the coat and anhedonia. Although, this environmental intervention did not produce significant changes in the neurogenic process affected by chronic mild stress, fluoxetine plus environmental enrichment showed similar effects to those caused by environmental enrichment to reverse depressive-like behaviors. Like fluoxetine, the combination reversed the declining number of Ki67, doublecortin, calretinin cells and mature newborn neurons. Finally, this study suggests that short daily exposure to environmental enrichment improves the effects of fluoxetine to reverse the deterioration of the coat and anhedonia in chronically stressed mice. In addition, the combination of fluoxetine with environmental enrichment produces more significant effects than those caused by fluoxetine alone on some events of the neurogenic process. Thus, environmental enrichment improves the benefits of pharmacological treatment by mechanisms that need to be clarified.
Assuntos
Anedonia/efeitos dos fármacos , Fluoxetina/farmacologia , Hipocampo/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Estresse Psicológico/fisiopatologia , Anedonia/fisiologia , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Calbindina 2/metabolismo , Proliferação de Células , Proteína Duplacortina/metabolismo , Meio Ambiente , Feminino , Hipocampo/metabolismo , Hipocampo/patologia , Antígeno Ki-67/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Estresse FisiológicoRESUMO
The amyloid beta-peptide (Aß) is the low-abundance product of amyloid precursor protein (APP), which is produced lifelong in the healthy brain. The functional properties of Aß40 and Aß42 peptides have not been completely elucidated to date. Although, several studies suggest that these peptides have a number of neurotrophic and neurotoxic properties, respectively. Interestingly, low concentrations of Aß40 and Aß42 regulate synaptic plasticity and improve cognitive functions, whereas the accumulation of Aß42, coupled with the effects of age, can cause dysregulation of synaptic function, as is shown in Alzheimer's disease. Additionally, several studies suggest that both peptides, Aß40 and Aß42, are involved in neurogenic processes; however, these results are still controversial. Moreover, existing data indicate a direct relationship between the physicochemical characteristics of the peptides and their effects. Herein, we evaluated the effect of Aß40 oligomers on hippocampal precursor cells isolated from the dentate gyrus of adult female C57Bl6 mice (mADGPCs). To this end, mADGPCs were treated with nanomolar and micromolar range concentrations of oligomeric forms of Aß40 for 24, 48, and 72 h to evaluate their effects on several events in the neurogenic process in vitro, including viability, proliferation, and early differentiation. The results indicate that Aß40 favors mADGPC proliferation, survival, and neuronal differentiation following a mechanism that involves activation of the Akt signaling pathway. Thus, this study provides evidence about the positive effects of Aß40 oligomers on the neurogenic process in adult mouse hippocampal precursor cells in vitro.
Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Diferenciação Celular/fisiologia , Neurônios/metabolismo , Animais , Hipocampo/metabolismo , Camundongos Endogâmicos C57BL , Neurogênese/fisiologia , Fragmentos de Peptídeos/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
Depression may be precipitated by the negative impact of chronic stress, which is considered to play a key role in this neuropsychiatric disorder. Interestingly, depressed patients show decreased levels of melatonin. This hormone acts pro-neurogenic and exhibits anti-depressant effects in rodent models of predictive antidepressant-like effects. However, the benefits of melatonin in reversing the deleterious effects of chronic mild stress on the alterations in behaviour and in the neurogenic niche of the hippocampus in male BALB/c mice are unknown. In this study, we compared the effects of melatonin (2.5â¯mg/kg) and citalopram (5â¯mg/kg), an antidepressant drug belonging to the selective serotonin reuptake inhibitors, in male BALB/c mice exposed to chronic mild stress (CMS). We also investigated the potential effects of melatonin and citalopram on microglial cells, hippocampal neurogenesis and peripheral cytokine profiles. Melatonin and citalopram induced similar antidepressant-like activities that occurred with some of the the following findings: (1) reversal of the morphological alterations in microglia; (2) reversal of the decreased immunoreactivity to CX3CL1 and CX3CR1 in the dentate gyrus; (3) positive regulation of cell proliferation, survival and complexity of the dendritic trees of doublecortin-cells; and (4) modifications of peripheral CX3CL1 expression. This outcome is consistent with the hypothesis about the antidepressant-like effect of melatonin and supports its relevance as a modulator of the niche in the dentate gyrus.
Assuntos
Quimiocina CX3CL1 , Melatonina , Animais , Depressão/tratamento farmacológico , Hipocampo , Masculino , Melatonina/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Microglia , NeurogêneseRESUMO
Adult neurogenesis occurs in the dentate gyrus (DG) of the hippocampus. New neurons help to counteract the effects of stress and several interventions including antidepressant drugs, environmental modifications and internal factors act pro-neurogenic with consequences in the dorsal and ventral DG. Melatonin, the main product synthesized by the pineal gland, induces antidepressant-like effects and modulates several events of the neurogenic process. However, the information related to the capability of melatonin to modulate dendrite maturation and complexity in the dorsal and ventral regions of the DG and their correlation with its antidepressant-like effect is absent. Thus, in this study, we analyzed the impact of melatonin (0, 0.5, 1, 2.5, 5 or 10 mg/kg) administered daily for fourteen days on the number, dendrite complexity and distribution of doublecortin (DCX)-cells in the dorsal-ventral regions of the DG in male Balb/C mice. Doublecortin is a microtubule-associated protein that is expressed during the course of dendritic maturation of newborn neurons. Also, we analyzed the impact of melatonin on despair-like behavior in the forced swim test. We first found a significant increase in the number and higher dendrite complexity, mainly with the doses of 2.5, 5 and 10 mg/kg of melatonin (81%, 122%, 78%). These cells showed more complex dendritic trees in the ventral- and the dorsal- DG. Concomitantly, the doses of 5 and 10 mg/kg of melatonin decreased depressant-like behavior (76%, 82%). Finally, the data corroborate the antidepressant-like effect of melatonin and the increasing number of doublecortin-associated cells. Besides, the data indicate that melatonin favors the number and dendrite complexity of DCX-cells in the dorsal- and ventral- region of the DG, which may explain part of the antidepressant-like effect of melatonin.
Assuntos
Antidepressivos/uso terapêutico , Dendritos/efeitos dos fármacos , Dendritos/metabolismo , Giro Denteado/efeitos dos fármacos , Giro Denteado/metabolismo , Melatonina/uso terapêutico , Animais , Depressão/tratamento farmacológico , Depressão/metabolismo , Proteínas do Domínio Duplacortina , Proteína Duplacortina , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Associadas aos Microtúbulos/metabolismo , Neurogênese/efeitos dos fármacos , Neuropeptídeos/metabolismoRESUMO
Neurogenesis in the hippocampus is influenced by several factors including external stimuli. In addition to their involvement in learning and memory processes, newborn neurons of the dentate gyrus (DG) buffer against the effects of stress. Although the response of these cells to environmental stimuli has been shown, the age of the cells that respond to a brief spatial exploration or a stressful situation produced by forced-swim stress in adult female Balb/C mice is still unknown. Here, we investigated the activation of newborn neurons after three (IdU) or six weeks (CldU) postlabelling with the expression of Arc in the same mice but exposed to different environmental stimuli. Mice housed in standard conditions showed an increase in the activation of CldU-labelled cells after two exposures to a brief spatial exploration but no increase in the activation of IdU-labelled cells compared with the control group. Additionally, we analysed neuronal activation in the DG of mice housed in standard conditions and further exposed to forced-swim stress. We found a decreased activation of IdU-labelled cells in mice exposed to forced-swim stress with increase number of CldU-labelled cells. Our results suggest that based on their time postlabelling, newly generated hippocampal neurons show a different response to several environmental stimuli.
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Giro Denteado/fisiologia , Comportamento Exploratório , Neurogênese , Neurônios/fisiologia , Comportamento Espacial , Estresse Psicológico , Animais , Proteínas do Citoesqueleto/metabolismo , Giro Denteado/metabolismo , Feminino , Camundongos Endogâmicos BALB C , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , NataçãoRESUMO
Neurogenesis plays a significant role during adulthood, and the observation that neural stem cells reside in the central nervous system and the olfactory epithelium has attracted attention due to their importance in neuronal regeneration. In addition, soluble factors (SFs) release by neural stem cells may modulate the neurogenic process. Thus, in this study, we identified the SFs released by olfactory human neural stem/progenitor cells (hNS/PCs-OE). These cells express Ki67, nestin, and ßIII-tubulin, indicating their neural lineage. The hNS/PCs-OE also express PSD95 and tau proteins during proliferation, but increased levels are observed after differentiation. Thus, we evaluated the effects of SFs from hNS/PCs-OE on the viability, proliferation, and differentiation potential of adult murine hippocampal neural precursor cells (AHPCs). SFs from hNS/PCs-OE maintain cells in the precursor and proliferative stages and mainly promote the astrocytic differentiation of AHPCs. These effects involved the activation, as measured by phosphorylation, of several proteins (Erk1/2; Akt/PRAS40/GSK3ß and JAK/STAT) involved in key events of the neurogenic process. Moreover, according to the results from the antibody-based microarray approach, among the soluble factors, hNS/PCs-OE produce interleukin-6 (IL-6) and neurotrophin 4 (NT4). However, residual epidermal growth factor (EGF) was also detected. These proteins partially reproduced the effects of SFs from hNS/PCs-OE on AHPCs, and the mechanism underlying these effects is mediated by Src proteins, which have been implicated in EGF-induced transactivation of TrkB receptor. The results of the present study suggest the potential use of SFs from hNS/PCs-OE in controlling the differentiation potential of AHPCs. Thus, the potential clinical relevance of hNS/PCs-OE is worth pursuing.
Assuntos
Linhagem da Célula , Hipocampo/citologia , Células-Tronco Neurais/citologia , Mucosa Olfatória/citologia , Adulto , Animais , Anticorpos Neutralizantes/farmacologia , Astrócitos/citologia , Astrócitos/efeitos dos fármacos , Biomarcadores/metabolismo , Diferenciação Celular/efeitos dos fármacos , Linhagem da Célula/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Citocinas/metabolismo , Fator de Crescimento Epidérmico/farmacologia , Receptores ErbB/metabolismo , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Fosforilação/efeitos dos fármacos , Receptor trkB/metabolismo , Solubilidade , Ativação Transcricional/efeitos dos fármacosRESUMO
Several interventions have been shown to counteract the effects of stress that may be related to improved neuroplasticity and neuronal activation. In this sense, environmental enrichment (ENR) protects against acute stress and increases neuroplasticity. It has been suggested that the use of patterned auditory stimuli (PAS) may be beneficial in increasing the effectiveness of ENR on disorders related to stress, such as depression and anxiety. Examples of PAS are classical music compositions that have interesting effects at both clinical and preclinical levels. Thus, we analyzed the effects of the exposure to PAS, represented in this study by Mozart's compositions, during ENR housing for 35 days in adult male Balb/C mice to evaluate depression-associated behavior using the forced-swim test (FST) paradigm with an additional short exposure to PAS. We found that the ENR mice that were exposed to PAS during both housing and behavioral task (ENR + PAS/FST + PAS) show decreased immobility and the number of despair episodes within a higher latency to show the first bout of immobility. Additionally, we found increased neuronal activation evaluated by the identification of activity-regulated cytoskeleton-associated protein- (Arc-) labeled cells in the prefrontal cortex (PFC) in mice exposed to PAS during housing and in the absence or presence of PAS during FST. Moreover, we found increased neuronal activation in the auditory cortex (AuCx) of mice exposed to PAS during FST. Our study suggests that the exposure to PAS during an emotional challenge decreases despair-like behavior in rodents that were previously housed in an enriched environment in combination with auditory stimuli. Thus, our data indicate that the role of the exposure to PAS as an intervention or in combination with positive environment to aid in treating neuropsychiatric disorders is worth pursuing.
Assuntos
Estimulação Acústica/métodos , Depressão , Abrigo para Animais , Estresse Fisiológico/fisiologia , Estresse Psicológico/fisiopatologia , Animais , Corticosterona/sangue , Meio Ambiente , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neurônios/fisiologia , Estresse Psicológico/psicologia , NataçãoRESUMO
Neurogenesis constitutively occurs in the olfactory epithelium of mammals, including humans. The fact that new neurons in the adult olfactory epithelium derive from resident neural stem/progenitor cells suggests a potential use for these cells in studies of neural diseases, as well as in neuronal cell replacement therapies. In this regard, some studies have proposed that the human olfactory epithelium is a source of neural stem/progenitor cells for autologous transplantation. Although these potential applications are interesting, it is important to understand the cell biology and/or whether human neural stem/progenitor cells in the olfactory epithelium sense external signals, such as brain-derived neurotrophic factor (BDNF), that is also found in other pro-neurogenic microenvironments. BDNF plays a key role in several biological processes, including cell migration. Thus, we characterized human neural stem/progenitor cells derived from the olfactory epithelium (hNS/PCs-OE) and studied their in vitro migratory response to BDNF. In the present study, we determined that hNS/PCs-OE express the protein markers Nestin, Sox2, Ki67 and ßIII-tubulin. Moreover, the doubling time of hNS/PCs-OE was approximately 38h. Additionally, we found that hNS/PCs-OE express the BDNF receptor TrkB, and pharmacological approaches showed that the BDNF-induced (40ng/ml) migration of differentiated hNS/PCs-OE was affected by the compound K252a, which prevents TrkB activation. This observation was accompanied by changes in the number of vinculin adhesion contacts. Our results suggest that hNS/PCs-OE exhibit a migratory response to BDNF, accompanied by the turnover of adhesion contacts.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/farmacologia , Movimento Celular/efeitos dos fármacos , Células-Tronco Neurais/efeitos dos fármacos , Mucosa Olfatória/citologia , Receptor trkB/metabolismo , Carbazóis/farmacologia , Adesão Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Colchicina/farmacologia , Inibidores Enzimáticos/farmacologia , Histonas/metabolismo , Humanos , Alcaloides Indólicos/farmacologia , Antígeno Ki-67/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Fatores de Tempo , Tubulina (Proteína)/metabolismo , Vinculina/metabolismoRESUMO
The generation of new neurons during adulthood involves local precursor cell migration and terminal differentiation in the dentate gyrus. These events are influenced by the hippocampal microenvironment. Brain-derived neurotrophic factor (BDNF) is relevant for hippocampal neuronal development and behavior. Interestingly, studies that have been performed in controlled in vitro systems that involve isolated precursor cells that were derived from the dentate gyrus (AHPCs) have shown that BDNF induces the activation of the TrkB receptor and, consequentially, might activate signaling pathways that favor survival and neuronal differentiation. Based on the fact that the cellular events of AHPCs that are induced by single factors can be studied in this controlled in vitro system, we investigated the ability of BDNF and the involvement of protein kinase C (PKC), as one of the TrkB-downstream activated signaling proteins, in the regulation of migration, here reflected by motility, of AHPCs. Precursor cells were cultured following a concentration-response curve (1-640 ng/ml) for 24 or 96 h. We found that BDNF favored cell survival without altering the viability under culture proliferative conditions of the AHPCs. Concomitantly, glial- and neuronal-differentiated precursor cells increased as a consequence of survival promoted by BDNF. Additionally, pharmacological approaches showed that BDNF (40 ng/ml)-induced migration of AHPCs was blocked with the compounds K252a and GF109203x, which prevent the activation of TrkB and PKC, respectively. The results indicate that in the in vitro migration of differentiated AHPCs it is involved the BDNF and TrkB cascade. Our results provide additional information about the mechanism by which BDNF impacts adult neurogenesis in the hippocampus.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Movimento Celular/fisiologia , Sobrevivência Celular/fisiologia , Hipocampo/metabolismo , Neurogênese/fisiologia , Neurônios/metabolismo , Células-Tronco Adultas/citologia , Células-Tronco Adultas/efeitos dos fármacos , Células-Tronco Adultas/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/administração & dosagem , Carbazóis/farmacologia , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Inibidores Enzimáticos/farmacologia , Feminino , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Alcaloides Indólicos/farmacologia , Indóis/farmacologia , Maleimidas/farmacologia , Camundongos Endogâmicos C57BL , Células-Tronco Neurais/citologia , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Neurogênese/efeitos dos fármacos , Neuroglia/citologia , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Neurônios/citologia , Neurônios/efeitos dos fármacos , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/metabolismo , Receptor trkB/antagonistas & inibidores , Receptor trkB/metabolismoRESUMO
Because stress may underlie the presence of depressive episodes, strategies to produce protection against or to reverse the effects of stress on neuroplasticity and behavior are relevant. Preclinical studies showed that exposure to stimuli, such as physical activity and environmental enrichment (ENR), produce beneficial effects against stress causing antidepressant-like effects in rodents. Additionally, ENR induces positive effects on neuroplasticity, neurochemistry and behavior at any age of rodents tested. Here, we analyzed whether ENR exposure prevents the development of depressive-like behavior produced by unpredictable, chronic mild stress (CMS) exposure as well as changes in hippocampal neurogenesis in a six-month-old female Balb/C mice, strain that shows low baseline levels of hippocampal neurogenesis. Mice were assigned to one of four groups: (1) normal housing-normal housing (NH-NH), (2) NH-CMS, (3) ENR-NH, or (4) ENR-CMS. The animals were exposed over 46 days to ENR or NH and subsequently to NH or CMS for 4 weeks. ENR induces long-term effects protecting against CMS induction of anhedonia and hopelessness behaviors. Independent of housing conditions, ENR increased the number of proliferative cells (Ki67), and CMS decreased the number of proliferative cells. ENR increased the newborn cells (BrdU) and mature phenotypes of neurons; these effects were not changed by CMS exposure. Similarly, the number of doublecortin-positive cells was not affected by CMS in ENR mice, which showed more cells with complex dendrite arborizations. Our study suggests that ENR induces protection against the effects of CMS on behavior and neuroplasticity in six-month-old Balb/C mice.
Assuntos
Meio Ambiente , Neurônios/fisiologia , Estresse Psicológico/fisiopatologia , Estresse Psicológico/terapia , Anedonia/fisiologia , Animais , Análise Química do Sangue , Bromodesoxiuridina , Proliferação de Células/fisiologia , Doença Crônica , Corticosterona/sangue , Giro Denteado/patologia , Giro Denteado/fisiopatologia , Transtorno Depressivo/patologia , Transtorno Depressivo/fisiopatologia , Transtorno Depressivo/terapia , Proteínas do Domínio Duplacortina , Ensaio de Imunoadsorção Enzimática , Feminino , Abrigo para Animais , Imuno-Histoquímica , Camundongos Endogâmicos BALB C , Proteínas Associadas aos Microtúbulos/metabolismo , Células-Tronco Neurais/fisiologia , Neurogênese/fisiologia , Neurônios/patologia , Neuropeptídeos/metabolismo , Estresse Psicológico/patologiaRESUMO
Melatonin is involved in the regulation of hippocampal neuronal development during adulthood. Emerging evidence indicates that exogenous melatonin acts during different events of the neurogenic process and exerts antidepressant-like behavior in rodents. Thus, melatonin might act through different mechanism, including acting as an antioxidant, interacting with intracellular proteins and/or activating membrane receptors. The melatonin membrane receptors (MMRs; Mt1/Mt2) are distributed throughout the hippocampus with an interesting localization in the hippocampal neurogenic microenvironment (niche), suggesting the involvement of these receptors in the beneficial effects of melatonin on hippocampal neurogenesis and behavior. In this study, we analyzed the participation of MMRs in the baseline neurogenesis in C57BL/6 mice. To this end, we used a pharmacological approach, administering luzindole (10 mg/kg) for 14 days. We observed a decrease in the absolute number of doublecortin-positive cells (49%) without changes in either the dendrite complexity of mature doublecortin-cells or the number of apoptotic cells (TUNEL). However, after the chronic administration of luzindole, cell proliferation (Ki67) significantly decreased (36%) with increasing (>100%) number of neural stem cells (NSCs; GFAP(+)/Sox2(+)) in the subgranular zone of the dentate gyrus of the hippocampus. In addition, luzindole did not affect hopelessness-like behavior in the forced swim test (FST) or changes in the novelty suppressed feeding test (NST) after 14 days of treatment either neuronal activation in the dentate gyrus after FST. These results suggest that the MMRs are involved in the effects of endogenous melatonin to mediate the transition from NSCs and proliferative cells to the following developmental stages implicated in the hippocampal neurogenic process of adult female C57BL/6 mice.
Assuntos
Depressão/fisiopatologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Neurogênese/efeitos dos fármacos , Receptores de Melatonina/antagonistas & inibidores , Receptores de Melatonina/fisiologia , Triptaminas/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Hipocampo/citologia , Camundongos , Camundongos Endogâmicos C57BL , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/fisiologia , Neurônios/citologia , Neurônios/fisiologiaRESUMO
Estrogens and antidepressants synergize to reduce depressive symptoms and stimulate neurogenesis and neuroplastic events. The aim of this study was to explore whether the antidepressant-like effect induced by the combination of low doses of estradiol (E2) and fluoxetine (FLX) involves changes in cell proliferation, early survival, morphology and dendrite complexity of hippocampal new-immature neurons. The antidepressant-like effects of E2 and/or FLX were evaluated by the forced swimming test (FST), cell proliferation was determined with the endogenous marker Ki67, survival of newborn cells was established with bromo-deoxiuridine (BrdU) and immature neurons were ascertained by doublecortin (DCX) labeling while their dendrite complexity was evaluated with Sholl analysis. Ovariectomized Wistar rats were randomly assigned to one of the following groups: Vehicle (saline/14 days+Oil/-8h before FST); E2 (saline/14 days + E2 2.5 or 10 µg/rat; -8 h before FST); FLX (1.25 or 10 mg/kg for 14 days + oil -8h before FST), and FLX plus E2 (FLX 1.25 mg/kg for 14 days + E2 2.5 µg/rat -8 h before FST). The combination of sub-threshold doses of FLX plus E2 produced antidepressant-like actions similar to those induced by FLX or E2 given independently at optimal doses. Only FLX at an optimal dose and the combination of FLX plus E2 increased cell proliferation, the number of DCX-labeled immature neurons and the complexity of their dendritic tree, suggesting that these events may be responsible for their antidepressant-like effect.
Assuntos
Antidepressivos/farmacologia , Estradiol/metabolismo , Estradiol/farmacologia , Fluoxetina/farmacologia , Hipocampo/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Proteína Duplacortina , Sinergismo Farmacológico , Feminino , Hipocampo/citologia , Ovariectomia , Distribuição Aleatória , Ratos , Ratos WistarRESUMO
Williams syndrome (WS) is a neurodevelopmental genetic disorder, due to a 7q11.23 hemizygous deletion. WS has a characteristic neurocognitive profile that includes intellectual disability (ID). Haploinsufficiency of some of the deleted genes is partially associated with the cognitive phenotype. The aim of this paper is to determine the differences in the microRNA (miRNA) expression in WS patients, using a neural cell model from the patients olfactory neuroepithelium (ONE), and to establish the relationship with those genes involved in neurodevelopment and neural function. To assess these goals, we made a comparative analysis of the miRNAs expression profile between WS patients and controls. Through an in silico analysis, we established potential pathways and targets associated with neural tissue. The expression profile shows 14 dysregulated miRNAs, including nervous system (NS)-rich miRNAs such as miR-125b, let-7c and miR-200. Most of these miRNAs have potential targets associated with NS functions while others have been reported to have specific neuronal functions. These data suggest that miRNAs widely contribute to the regulation of neurodevelopmental intrinsic processes, and that specific miRNAs could participate in WS neurobiology.
Assuntos
MicroRNAs/fisiologia , Modelos Biológicos , Células-Tronco Neurais/citologia , Síndrome de Williams/patologia , Adolescente , Adulto , Sequência de Bases , Estudos de Casos e Controles , Criança , Primers do DNA , Feminino , Humanos , MicroRNAs/genética , Reação em Cadeia da PolimeraseRESUMO
Neuropsychiatric diseases (NPD) are characterized by changes in brain plasticity involving alterations in the morphology and functionality of neurons. However, affectations of the neuronal development (neurogenesis) in the adult brain are also shown. The neurogenic process is widely regulated by different factors such as genes, microenvironment, hormones, neurotransmitters, environmental cues and, also, nutrition. Thus, alterations in these factors negatively impact the neuronal development. Several studies performed in humans have revealed alterations of neurogenesis in NPD. However, most of the knowledge derives from studies done in animal models of NPD. The evidences from animal models are controversial, thus the use of human-induced pluripotent stem cells as a model of NPD has marked a way to study alterations in the neuronal development. Recently, the use of another cellular model for studying NPD has been proposed. Multipotent stem cells derived from olfactory epithelium (MOESCs) are a good candidate. However, evidences are scarce and deeper studies are necessary to know if there is or not a correlation of alterations in neuronal development in the OE with the changes observed in the brain; or if the MOESCs can mimic alterations shown in NPD that could let to get more knowledge about the factors promoting these diseases. Thus, in this review we discuss basic information about adult neurogenesis under physiological and non-physiological conditions in the hippocampus, olfactory bulb and olfactory epithelium.
Las enfermedades neuropsiquiátricas (ENP) se caracterizan por cambios en la plasticidad cerebral que incluyen la pérdida neuronal en regiones específicas en el encéfalo, cambios en la transmisión sináptica originada por alteraciones en los contactos sinápticos y también por la expresión de genes. Además, otro proceso que forma parte de la plasticidad cerebral y que también se encuentra afectado en las ENP es la generación de nuevas neuronas (neurogénesis). El proceso neurogénico en el adulto es regulado de manera fina por diversos factores como los aspectos genéticos, celulares, el microambiente, los elementos neuroquímicos, los ambientales y los nutricionales. Las alteraciones de estos factores impactan en el desarrollo y en la función de las nuevas neuronas. Algunos estudios realizados en humanos han revelado las alteraciones en la neurogénesis en algunos ENP. Sin embargo los mayores avances logrados han utilizado modelos animales de ENP. En algunos casos estas evidencias son controvertidas y recientemente se han tratado de aclarar utilizando cultivos de células madre pluripotenciales-inducibles humanas como modelos de ENP. Otro modelo que se ha propuesto para estudiar las alteraciones en el desarrollo neuronal en las ENP son las células madre multipotenciales del epitelio olfatorio (CMPEO). Sin embargo las evidencias obtenidas con las CMPEO son escasas y resulta necesario demostrar si existe o no un correlato con las alteraciones que ocurren en el desarrollo neuronal a nivel central en las ENP, o bien si las CMPEO pueden mostrar las alteraciones observadas en las ENP que permitan obtener información acerca de los factores que promueven estas enfermedades. Por lo tanto en esta revisión se incluyen aspectos básicos de la neurogénesis e información relevante de las alteraciones de este proceso en las tres regiones neurogénicas en el adulto: el hipocampo, el bulbo olfatorio y el epitelio olfatorio.
RESUMO
Most studies relating experimental depression and neurogenesis use mainly male rodents subjected to models of chronic stress. The forced swimming test (FST) is a widely utilized model of acute stress, but its effects on the neurogenic process in the hippocampus using females in different endocrine conditions has not been explored. The aim of this study was to evaluate the cell proliferation and early-, short- and long-lasting effects of forced swimming (FS) on adult hippocampal neurogenesis in rats in two endocrine conditions: proestrous and ovariectomized. To determine cell proliferation we used the endogenous marker Ki67. Cell survival was established with the thymidine analog, BrdU (75mg/kg, 2/12, i.p.), which was administered before FS to proestrous and ovariectomized rats. FS increased immobility and corticosterone levels in OVX but not in rats in proestrus. In addition, FS did not affect cell proliferation but significantly decreased the number of BrdU-labeled cells at 2h only in OVX-rats, an effect that remained for 3 and 14 days after FS. Data are discussed taking into consideration the relationship between gonadal and adrenal hormones in adult hippocampal neurogenesis in adult females. Our data also support the use of FS as a model for studying neurogenesis.
Assuntos
Hipocampo/citologia , Resposta de Imobilidade Tônica/fisiologia , Neurogênese/fisiologia , Ovariectomia , Estresse Psicológico/fisiopatologia , Animais , Sobrevivência Celular/fisiologia , Corticosterona/sangue , Feminino , Hipocampo/fisiologia , Proestro/metabolismo , Proestro/fisiologia , Ratos , Estresse Psicológico/sangue , Natação , Fatores de TempoRESUMO
Estrogens produce a wide range of biological effects throughout the body, including the Central Nervous System (CNS). In the brain, besides acting as neuroprotective agents, estrogens play an important role in many neuronal processes and certain psychiatric disorders such as depression. The precise mechanism by which estrogens induce their positive effects on depressive disorders has not been elucidated; however, it is known that estrogens act on the CNS through the activation of specific receptors. These actions occur in genomic and non-genomics mechanisms through the modulation of synthesis and metabolism of neurotransmitters, neuropeptides, neurosteroids and influencing the morphological features of neurons and synaptic function. In addition, it is known that estrogens can act as modulators of processes related to neuroplasticity and neurogenesis. Adult hippocampal neurogenesis is a neuroplastic process that is affected by antidepressant drugs. These drugs increase the number of new neurons following a temporal course that correlates within the time in which antidepressants cause a behavioral improvement in rodents and in humans. Interestingly, whereas the behavioral antidepressant effects require 2-4 weeks to appear, after treatment initiation, estrogen reduce the depressive-like behavior and induce cell proliferation in terms of days. Thus, antidepressant drugs and the estrogens replacement during the adulthood could influence in a similar manner the new neuron formation. Furthermore, recent works have indicated that the combination of antidepressants plus estrogens could exert beneficial actions at lower doses of estrogens (physiological range). This evidence is important due to the combination of non-effective doses of antidepressants plus estrogens could decrease the side-effects of both compounds, and facilitate the behavioral action of antidepressant drugs shortening the latency to onset their action. The present review discusses recent information about the implication of estrogens in depression, and on their effects as positive regulators of new neuron formation in the adult hippocampus. In addition, we will review the possible implication of last effect of estrogens on their antidepressant effects.
Los estrógenos producen una amplia gama de efectos biológicos en todo el cuerpo, incluyendo el Sistema Nervioso Central (SNC). En el cerebro, además de actuar como agentes neuroprotectores, los estrógenos desempeñan un papel importante en la regulación de procesos neuronales constituyéndose así como posibles factores relacionados con la etiología de algunos trastornos neuropsiquiátricos, tales como la depresión. Durante los últimos años se ha generado evidencia de la relación existente entre los niveles fisiológicos de los estrógenos y el desarrollo de episodios depresivos. Por otra parte, los estrógenos tienen un papel importante en la inducción de cambios a nivel de la plasticidad neuronal y de la neurogénesis en el hipocampo adulto. A este respecto se ha observado que los estrógenos regulan el desarrollo, la maduración y la sobrevivencia de las nuevas neuronas en el cerebro adulto, de la misma manera que lo hacen los tratamientos antidepresivos. Los efectos de los estrógenos sobre la neurogénesis y la plasticidad neuronal podrían estar regulados por los receptores a estrógenos, tanto el receptor alfa (REα), como el receptor beta (REβ). Ambos subtipos de receptores se expresan en el hipocampo del cerebro adulto. Así mismo, el hipocampo es una estructura que participa en procesos cognitivos y de memoria y existe evidencia que muestra su participación en la etiología de la depresión y sobre el efecto de los fármacos antidepresivos. La neurogénesis ha sido considerada como un proceso dinámico por medio del cual se forman neuronas funcionales. De tal modo que este proceso también involucra los eventos de sobrevivencia, maduración dendrítica y axonal, así como el establecimiento de conexiones sinápticas para la integración final de las nuevas neuronas en los circuitos neuronales existentes, eventos que son modulados por los fármacos antidepresivos. En el presente artículo se revisa información reciente acerca de los efectos de los estrógenos sobre la depresión y sobre su relación con la neurogénesis hipocámpica.